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Transcript
COPD and Co-morbidities: Chance or Fate?
Bartolome R. Celli, MD
Brigham and Women’s Hospital
Harvard Medical School
Boston
Chronic Obstructive Pulmonary Disease
• “Preventable and treatable disease
characterized by airflow limitation,
resulting from an abnormal
inflammatory reaction to inhaled
particles (smoking) and associated with
co-morbidities”
GOLD accessed May 2013
Co-morbidity in COPD
• In patients with COPD, not all CoMorbidites are created equal
• From the Solar System to the Milky
Way (Multi-morbidity)
• We need to re-think how we link
diseases….perhaps by pathobiology?
Co-morbidity in COPD
• In patients with COPD, not all CoMorbidites are created equal
• From the Solar System to the Milky
Way (Multi-morbidity)
• We need to re-think how we link
diseases….perhaps by pathobiology?
COPD
Lung cancer
9 - 20%
30%
Cachexia
30-50%
vs
myopathy Osteoporosis
20-60%
Anxiety and
30-50%
17%
CAD/CHF
Anemia
Barnes and Celli ERJ 2008
TORCH: Causes of death as
adjudicated by the Endpoint
Committee
Other
10%
Cancer
21%
Unknown
7%
Respiratory
35%
Cardiac
27%
Wise et al PATS 2006
Co-morbidities in patients with COPD
80
Attending P.R.
% of patients
2900 patients
60
40
Comorbidity impacted on
response to PR
Aim: Effect of comorbidities on
response to P.R.
20
0
FEV1 = 49%
> 1 Comorbidity
Metabolic
Heart Disease
Age = 71
Crisafulli et al Thorax. 2008;63:487
Divo et al AJRCCM 2012;186:155
Celiac disease
BOOP
Rectal cancer
Testicula cancer
HIV
Thyroid cancer
Brain cancer
Liver cancer
Kidney cancer
Inflamatory Bowel disease
Parkinson
MAI
Melanoma
Restless leg syndrome
Colon cancer
Pancreatitis
Bronchiectasis
Liver cirrhosis
Dementia
Connective Tissue disorders
Nephrolithiasis
Hepatitis
Neurophaty DM
Gout
Other arrythmia
DVT
Pulmonary fibrosis
Breast cancer
Osteoporosis
Prostate cancer
Pul HTN+CP
Emphysema
Erectile dysfunction
AF+Flutter
CHF
Deppresion
GERD
Degenerative joint disease
CAD+MI
HTN
Prevalence (%)
78 comorbidities
60
50
40
30
20
10
Prevalence (%)
0
Divo et al AJRCCM 2012;186:155
Co-morbidity in COPD
• In patients with COPD, not all CoMorbidites are created equal
• From the Solar System to the Milky
Way (Multi-morbidity)
• We need to re-think how we link
diseases….perhaps by pathobiology?
New Concepts: Network Medicine
Barabasi A.L. NEJM 2007;357:4
Dynamic Network Approach for
the Study of Human Phenotypes
Hidalgo et al PLoS Comput Biol 5(4):2009
Dynamic Network Approach for
the Study of Human Phenotypes
Hidalgo et al PLoS Comput Biol 5(4):2009
Definitions
Co-morbidity relationship
exists between two diseases
whenever they affect the same
individual substantially more
than chance alone
Hidalgo et al PLoS Comput Biol 5(4):2009
The COPD (Comorbidity + Clinical Characteristics) Network
•
•
86 Nodes
• 79 Comorbidities
• 7 Clinical characteristics
520 Connections
+
50%
Divo et al (BODE COHORT)
Motif 1
10%
Divo et al (BODE COHORT)
Motif 2
10%
Divo et al (BODE COHORT)
Motif 3
10%
Objectives
• COPD and Lung Cancer: Big
Problems
• One agent, two diseases……or is it?
• Pathobiological symbiosis
• Facing the problem
Objectives
• COPD and Lung Cancer: Big
Problems
• One agent, two diseases……or is it?
• Pathobiological symbiosis
• Facing the problem
Top 10 Causes of Death, Years of Life Lost from Premature Death, Years Lived with Disability,
and Disability-Adjusted Life-Years (DALYs) in the United States, 2010.
Murray CJ, Lopez AD. N Engl J Med 2013;369:448-457.
Objectives
• COPD and Lung Cancer: Big
Problems
• One agent, two diseases……or is it?
• Pathobiological symbiosis
• Facing the problem
Airflow obstruction and lung
Cancer
1.Skillrud DM Ann Intern Med 1986;105:503
2. Tockman MS. Ann Intern Med 1987; 106:512
Lung Cancer in Bullous
Emphysema
Goldstein M, Snider GLS et al Am Rev Respir Dis 1968;97:1062
Assessing the relationship between lung cancer risk
and emphysema detected on low-dose CT of the chest
Number = 1,666 ever-smokers. Screened for Cancer.
Spain
Odds Ratio for a diagnosis of lung cancer
RR
IC 95%
Emphysema
2,51
1,01– 6,23
COPD
2,10
0,79 – 5,58
Adjusted for age, sex and pack-years, emphysema or COPD.
de Torres et al. CHEST 2007; 132: 1932-8
Number = 3,678 screened for lung cancer.
Pittsburgh.
OR
95%CI
Emphysema
3.14
1.91– 5.15
COPD
1.41
0.87- 2.29
Adjusted for age, sex and smoking and emphysema or COPD
Wilson et al Am J Respir Crit Care Med 2008;178:738
BODE group
• 2507 pts mean follow up 60 months
• 215 cases of lung cancer (8,5%)
• Incidence density 1.67/100 persons year
• Most frequent histological type: squamous cell
• 904 died during the follow up time
• 174 due to lung cancer
de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9
Predictors of Lung Cancer development
de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9
Synergy and Convergence
Lung
Cancer
COPD
Objectives
• COPD and Lung Cancer: Big
Problems
• One agent, two diseases……or is it?
• Pathobiological symbiosis
• Facing the problem
Common Variants, Low Penetrance
GWAS in lung cancer with COPD phenotype considered:
SNP in Genes
CHRNA3/5
FAM13A
BAT3
TERT
HHIP
ADAM19
AGER
CRP
Phenotype
Lung cancer + COPD
Lung cancer + COPD
Lung cancer + COPD
Lung cancer
Lung cancer + COPD
Lung cancer + COPD
COPD
Lung cancer
(Young, PLoS ONE, 2011)
State of the Art
Oxidative stress
Cell replication and senescence
Gene expression
Epigenetics
Methylation
Endogenous modifiers
Co-morbidities
Microbiota
Pathobiological Symbiosis
Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7.
Pathobiological Symbiosis
Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7.
Pathobiological Symbiosis
Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7.
Objectives
• COPD and Lung Cancer: Big
Problems
• One agent, two diseases……or is it?
• Pathobiological symbiosis
• Facing the problem
Lung
Cancer
US
Co-morbidity in COPD
• In patients with COPD, not all CoMorbidites are created equal
• From the Solar System to the Milky
Way (Multi-morbidity)
• We need to re-think how we link
diseases….perhaps by pathobiology?
Genome
Environment
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
Genome
Environment
Transcriptome
Proteome
Metabolome
Thrombosis
Inflammation
Hemorrhage
Fibrosis
Immune
Cell
Apoptosis
response
proliferation
Necrosis
Abnormal organ function
Disease with different phenotypes
Modified from Loscalzo et al Mol Sys Bio 20007;3:124
A Road to the Future
• Some co-morbidities of COPD share
pathobiological responses to injurious agents
and occur more frequently than chance would
have it.
• We may have to shift from organ oriented
pathophysiology to mechanistic pathobiology
• Comprehensive evaluation of patients for
commonly occurring diseases
• Merging of specialties? Back to Holistic
Medicine
How do we do it?
Bench
scientist
Clinician
Data Integration Manager
Thank You
Nothing is impossible, the word
itself says, “I’m possible!” –
Audrey Hepburn